Osteoporosis is the most common form of metabolic bone disease. The term encompasses any disease or idiopathic cause that results in a reduction in the mass of bone per unit volume. Osteoporosis results in differing degrees of skeletal fragility sufficient to increase the risk of fracture. Typically, the resorption in bone mass results from an imbalance in the processes that influence the acquisition and maintenance of skeletal mass. Osteoporosis is the most common disorder in which all of the skeleton is. involved, and is an important cause of morbidity in the elderly. Post-menopausal women are at a particularly high risk for idiopathic osteoporosis.
In general, cancellous bone has higher turnover rate than cortical bone. In early years of menopause the rate of bone loss is substantially faster for vertebral cancellous bone than for cancellous bone at other sites and cortical bone. Usually, peak adult bone mass is reached between the ages of 30 and 35 for cortical bone and often even earlier for trabecular bone. After peak adult bone mass is reached, the rates of bone formation and resorption are typically approximately equal, and relatively low compared with the period of growth spurt. Normally, skeletal mass is maintained by the normal balance between bone formation and bone resorption.
Bone remodeling, including bone formation and resorption, is a continuous process. In healthy subjects, these complementary mechanisms maintain a steady bone mass per unit volume (referred to herein as “bone mass”). However, subjects that may have failed to obtain optimal skeletal mass during the first 30 years of life, and/or subjects wherein the rate of bone resorption exceeded the rate of bone formation after peak skeletal mass was obtained may develop osteoporosis.
Bone resorption typically precedes formation, but does not last as long as formation. As a result, there are typically more sites of active formation than of resorption. Unless formation compensates for resorption, the bone mass will decrease. After an age ranging from 40 to 50, cortical bone is lost at a rate of about 0.3 to 0.5% per year in both men and women. There is an accelerated loss of cortical bone superimposed on the age-related loss around the menopause in women. The cumulative losses of bone mass range from 20 to 30% in men and up to 50% in women. Remodeling activity is typically increased in women with post-menopausal osteoporosis, when compared with age-matched controls. The difference is even more striking when the bone remodeling activities of post-menopausal women are compared to pre-menopausal women. When the difference between the rates of bone formation and bone resorption is maintained, the loss of bone density may become so marked that the bone can no longer withstand normal mechanical forces to which it is subjected, resulting in bone fracture. Often, osteoporosis is only recognized as a clinical problem after a fracture has occurred.
In some instances, another disease, for example, Cushing's Syndrome or osteogenesis imperfecta, results in osteoporosis. In most cases, however, patients with osteoporosis do not appear to have any other disease. Osteoporosis, which occurs in children, young adults, and adults of both sexes with normal gonadal function, is referred to as idiopathic osteoporosis, although often the osteoporosis is of unknown pathogenesis.
There are agents available for preventing bone loss and treating established osteoporosis. The ability to measure bone density and predict bone fracture risk has changed the approach to treatment, as a clinical benefit of treatment can be measured in terms of improved bone mass as well as a decreased incidence of fractures. Most of the drugs that are available are inhibitors of bone resorption, although some agents, such as sodium fluoride, increase bone formation. Fluoride treatment suffers from a narrow therapeutic window and a lack of demonstration of reduction in fracture rate, probably due to the poor mechanical qualities of newly formed bone. The agents that are currently available and/or under investigation to treat osteoporosis include, but are not limited to, Selective Estrogen-Receptor Modulators (SERMs), estrogens, androgens, cathepsin K inhibitors, calcium supplements, vitamin D (and metabolites and analogs thereof, thiazide diuretics,-calcitonin (and analogs thereof), bisphosphonates, fluoride, integrin antagonists, parathyroid hormone, calcilytics, calcimimetics, inhibitors of Src tyrosine kinase and Src SH2 inhibitors.
However, the available agents to treat osteoporosis that are available to date suffer from several drawbacks. First, most available agents may inhibit bone resorption but do not promote bone formation. Additionally, many women are reluctant to use estrogens to prevent bone loss and/or treat osteoporosis because of the return of menstrual bleeding and the fear of an increased risk for endometrial and breast cancer. Testosterone has been shown to be useful to treat osteoporotic men with gonadal deficiency, but there has been no evidence of efficacy in men with no normal gonadal function. Some patients cannot tolerate the agents used to treat osteoporosis because of undesirable side-effects, such as knee, foot and ankle pain, and nausea. Additionally, none of the agents used to treat osteoporosis completely inhibit resorbtion and/or actively promote bone formation.
As a result, several groups have been investigating various types of agents to treat osteoporosis, alone, and in combination. Parathyroid hormone (PTH), parathyroid related-protein (PTHrP), and analogs thereof are among the many agents that have been proposed for the treatment of osteoporosis.
The normal function of PTH is to maintain extracellular fluid calcium concentration. PTH acts directly on bone and kidney and indirectly on the intestines. PTH production in healthy individuals is closely regulated by the concentration of serum ionized calcium. Tendencies towards hypocalcemia, for example, induced by a calcium-deficient diet, are balanced by an increased PTH secretion. The increase in PTH levels increases the rate of bone resorption, thereby increasing the calcium flow from bone into blood, reduces the renal clearance of calcium. and increases the efficiency of calcium absorption in the intestines.
The physiological role of the parathyroid hormone-related protein (PTHrP) is not fully understood, but is thought to be acting principally as a paracrine or autocrine factor. PTHrP plays a role in fetal development as well as in adult physiology. PTHrP is produced by many cell types, including brain, pancreas, heart, lung, memory tissue, placenta, endothelial, and smooth muscle cells. In adults, PTHrP is thought to have little to do with calcium homeostasis, except in disease states.
PTH and PTHrP are distinct proteins and products of different genes. However, they share a similar bioactivity profile and a very limited sequence homology, indicating that they may have evolved from a common ancestral gene. Eight out of the 13 first amino acid residues at the N-terminus are identical. Both PTH, an 84 amino acid residues peptide, and PTHrP, a 139 to 173 amino acid residues peptide, bind to the PTH receptor (often referred to as the PTH/PTHrP receptor) and stimulate the same intracellular signaling pathways.
The mature circulating form of parathyroid hormone is comprised of 84 amino acid residues. For most bone-related activities the truncated form of PTH, PTH(1-34), is a full agonist like the native 84 amino-acid hormone. Amino-terminal truncation results in polypeptides that are competitive antagonists of PTH-stimulated adenylate cyclase. For example, [Tyr34]bPTH(7-34)NH2 retains moderate affinity for renal PTH receptors, but does not have any agonist activity; weak receptor binding activity is retained in a fragment as small as PTH(25-34) (M. Rosenblatt, et al., Endocrinol., (1980)107, 545-550). In contrast, carboxyl-terminal truncations of PTH(1-34) produce agonists with progressively lower affinities. PTH(1 -25) is reported to be essentially inactive (Segre, G. V., et. al., J. Biol. Chem. (1979) 254, 6980-6996; Rosenblatt, M., Endocrinology of Calcium Metabolism; Parsons, J. A., ed. (1982) Ravens Press, N.Y., 103-142; Tregear, et al., Endocrinol. (1973) 93, 1349-1353). The principal receptor-binding domain of PTH is reported to include amino acid residues 25-34 and the principal activation domain is reported to include amino acid residues 1-6.
Under some circumstances, PTH is a bone anabolic agent, and promotes bone formation. However, PTH can stimulate bone resorption as well. It has been reported that high-dose, continuous administration of PTH results in a lowered bone mass but low-dose, intermittent administration of PTH can increase bone mass. PTH administered continuously reportedly causes an increase in the number of bone cells, including osteoclasts, and an increase in bone remodeling. These increases reportedly are apparent within hours after PTH administration and persist for hours after PTH is withdrawn. PTH administration intermittently over days in humans and animals reportedly leads to a net stimulation of bone formation. For example, see Neer et al., N. Engl. J Med. 344:1434-1441, (2001). In contrast, continuous exposure to elevated levels of PTH leads to osteoclast-mediated bone resorption. Several groups have investigated the use of PTH and PTHrP analogs as agents to treat osteoporosis. These efforts are described in U.S. Pat. Nos. 5,747,456; 5,849,695; 4,656,250; 6,051,686; and 6,316,410.
A need exists for pharmaceutical agents that can be used to treat osteoporosis. Preferably, such agents will have improved functional activity with minimum adverse side effects.